Status: The goal of this project is to generate new drug candidates that meet the target product profile for the treatment of VL. DNDi partnered in 2007 with Advinus Therapeutics, a drug discovery and development company based in Bangalore, India, and CDRI (Central Drug Research Institute), an Indian public institution located in Lucknow, India.
Compounds showing activities (hits) are identified from DNDi’s ongoing screening projects carried out by our screening partners. The chemical structure of the best hits are then systematically modified, guided by a combination of medicinal chemistry, physicochemical properties, biological screening, and absorption, distribution, metabolism, excretion, and toxicology (ADMET) parameters, to ensure that the optimized compounds meet all the necessary drug-like criteria specified by the target product profile (TPP) for a new drug to treat VL. With a full team of eight chemists in place within the VL Lead Optimization Consortium, assessments of four series of synthetic compounds, provided by DNDi partners, have been carried out or are ongoing.
Recently, the thiazole series identified from a large screening campaign performed at Institut Pasteur Korea (IPK) has yielded potent lead molecules. Additional efficacy and pharmacokinetics studies are underway to identify pre-clinical candidates from this promising series.

Status: With the objective of developing optimized leads by progressing “hit” molecules with a good safety profile and activity against T. brucei parasites, this consortium brings together expertise in chemistry, biology, screening, and pre-formulation. Optimization efforts are focused on improving the molecule’s capacity to be absorbed into the bloodstream, to be distributed effectively to the infection sites, to survive in the body, to kill the parasite, and not to harm the patient. With two full lead optimization teams in place at Scynexis (a total of 18 scientists), a number of hits identified from DNDi screening partners are undergoing hit expansion. Scientists within the consortium use advanced techniques to study how the selected molecules interact with the therapeutic target (i.e. a protein or an enzyme, if known) and optimize the drug-like characteristics of these molecules to ensure that they comply with the target product profile (TPP).
This phase of discovery work requires a close, highly interactive collaboration between the biologists and chemists, who form a feedback loop: the biologists test the biological properties of compounds on biological systems, while the chemists perfect the chemical structure of these compounds based on information obtained by the biologists. Many compound series have been assessed. The current focus of the team is on the oxaborole series (see below).
The nitroimidazole class is another chemical series that is promising. One of the compounds in this class, fexinidazole, has been advanced into clinical development. DNDi’s strategy for the Lead Optimization Consortium is to develop a back-up compound in each of the oxaborole and nitroimidazole series. In case of failure of one of the current developed compounds, the back-up should be able to replace it rapidly.